CN102603646B - Synthesis method of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole - Google Patents

Abstract

The invention discloses a novel synthesis method of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole and belongs to the technical field of organic chemical synthesis. The method comprises the following steps: carrying out reaction on thioanisole and acetyl chloride to generate 4-methylthioacetophenone, carrying out reaction on 4-methylthioacetophenone and methyl benzoate to generate 1-(4-methylthiophenyl)-3-phenyl-1,3-dione, carrying out reaction on 1-(4-methylthiophenyl)-3-phenyl-1,3-dione and tert-butyl nitrite to generate 1-(4-methylthiophenyl)-2-phenyl-1,2-dione, carrying out reaction on 1-(4-methylthiophenyl)-2-phenyl-1,2-dione and trifluoroacetaldehyde methyl hemiacetal to generate 4-[4-(methylthio)phenyl]-5-phenyl-2-(thrifluoromethyl)-1H-imidazole, and finally oxidizing to generate 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole. According to the invention, the synthesis method is adopted, the utilization of cyanide and the damage of KMnO4 to carbon-carbon double bond are avoided, so that the method has industrial application values.

Description

Synthesis of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole

technical field

The invention relates to the technical field of organic chemical synthesis, in particular to a method for synthesizing 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole.

Background technique

Prostaglandins play an important role in the production of inflammation, and inhibiting the production of prostaglandins is a basic way of anti-inflammatory drugs. But while common NSAIDs block inflammation by inhibiting prostaglandins, they also inhibit the normal physiological regulation of prostaglandins. Therefore, the use of high doses of anti-inflammatory drugs can lead to side effects, especially severe ulcers. Traditional NSAIDs work by blocking inflammation by inhibiting cyclooxygenase (COX), an enzyme involved in the production of prostaglandins.

Studies have shown that replacing COX by inhibiting another enzyme cyclooxygenase II (COX II) can achieve the purpose of preventing inflammation more efficiently and have fewer side effects (Proc.Natl.Acad.Sci, USA, 89, 7384 (1992) ). Richard M. Weier et al. (UsPat.No.5,620,999) found a class of imidazole derivatives. The imidazole derivatives have a structural formula as shown in formula (1), and the imidazole derivatives can inhibit COX II with high efficiency and high selectivity. , and has a small inhibitory effect on COX. Among them, the IC ₅₀ for COX II is less than 0.2 μM, and the selectivity is higher than 100.

At present, the synthesis methods of this class of imidazole compounds are reported as follows (U.s.Pat.No.5,620,999; Antiinflammatory 4,5-diarylimidazoles as selective cyclooxygenase inhibitors Bioorganic & Medicinal Chemistry Letters 8(24):3443-3448:)

(1) After condensation-oxidation-condensation ring-closing-oxidation process. This approach met the early needs, but the benzoin was condensed in one step, the reproducibility was poor, it was difficult to scale up, and highly toxic HCN was produced during the hydrolysis process, and the reaction process was shown in formula (2).

(2) After wittig reaction, two-step oxidation, and finally condensation and ring closure to obtain the final product. KMnO ₄ is used in this reaction route, which easily leads to the breakage of the carbon-carbon double bond, and the reaction process is shown in formula (3).

This reaction pathway is roughly the same as (2), except that in the wittig reaction, the substrates on both sides are exchanged in one step. Similarly, the disadvantage of this route is that _KMnO easily leads to the breakage of the carbon-carbon double bond, and its reaction process is as shown in formula (4) shown.

In short, the above three methods have their own disadvantages. In the former method, in the benzoin condensation step, the reaction repeatability is poor, it is difficult to scale up, and highly toxic HCN is produced during the hydrolysis process, which limits the application of this method; when the latter two methods are oxidized with KMnO ₄ , it may lead to carbon Breaking of the carbon double bond.

Contents of the invention

The present invention provides a method for synthesizing 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole, 1,3 diketone in cheap iron catalyst It is converted into 1,2 diketone under the action of cyanide, avoiding the use of cyanide and the destruction of KMnO ₄ , and has industrial application value.

A method for synthesizing 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole, comprising:

(1) Under the action of a catalyst, thioanisole and acetyl chloride react to generate 4-methylthioacetophenone, and the molar ratio of said thioanisole to the catalyst is 1: 1.1～3, preferably 1.1～2.5 , the mol ratio of sulfide anisole and acetyl chloride is 1: 0.5～2;

(2) under the action of a catalyst, the 4-methylthioacetophenone reacts with methyl benzoate to generate 1-(4-methylthiobenzene)-3-phenyl-1,3 diketone, the The molar ratio of 4-methylthioacetophenone and catalyst is 1: 2～4, and the mol ratio of 4-methylthioacetophenone and methyl benzoate is 1: 0.5～2;

(3) Under the action of a catalyst, the 1-(4-methylthiobenzene)-3-phenyl-1,3 diketone and tert-butyl nitrite react to generate 1-(4-methylthiobenzene) -2-phenyl-1,2 diketone, the molar ratio of the 1-(4-methylthiophenyl)-3-phenyl-1,3 diketone and the catalyst is 1:0.1～0.5,1- (4-methylthiophenyl)-3-phenyl-1,3 diketone and tert-butyl nitrite have a molar ratio of 1: 3～7;

(4) described 1-(4-methylthiophenyl)-2-phenyl-1,2 dione reacts with ammonium acetate and trifluoroacetaldehyde methyl hemiacetal to generate 4-[4-(methylthio Base) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole, the 1-(4-methylthiophenyl)-3-phenyl-1,2 dione and three The molar ratio of fluoroacetaldehyde methyl hemiacetal is 1:1.1～2, the molar ratio of 1-(4-methylthiophenyl)-3-phenyl-1,3 diketone and ammonium acetate is 1:1.1～ 4, preferably 1.1 to 3;

(5) The 4-[4-(methylthio)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole is oxidized by an oxidant to generate the 4-[4- (Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole, the 4-[4-(methylthio)phenyl]-5-phenyl-2 The molar ratio of -(trifluoromethyl)-1H-imidazole to oxidant is 1:1.8-2.2.

The catalyst described in the step (1) is aluminum trichloride, ferric chloride or zinc dichloride, and the reaction is carried out in organic solvents such as dichloromethane, chloroform or carbon disulfide; the reaction is incomplete when the reaction temperature is too low , when the reaction temperature is too high, impurities will be produced in the product, which will affect the yield of the product. Therefore, as a kind of preference, the reaction temperature in step (1) is 10～30° C.; the reaction time is not very influential on the yield Generally, the reaction time is controlled within 10-20 hours, usually overnight, within 10-20 hours.

The catalyst described in the step (2) is sodium hydride, sodium tert-butoxide, potassium tert-butoxide or lithium tert-butoxide, preferably sodium hydride, and the reaction is carried out in THF or N, N-dimethylformamide; When the temperature is too low, the reaction is incomplete, and when the reaction temperature is too high, impurities will be produced in the product, which will affect the yield of the product. Therefore, as a kind of preference, the reaction temperature in the step (2) is 50～70° C.; the reaction time It is 10-20 hours, and under normal circumstances, the reaction is overnight, and it can be within 10-20 hours.

The catalyst described in the step (3) is ferric trichloride, ferric tribromide, ferrous chloride or ferric oxide; when the reaction temperature is too low, the reaction is not complete, and when the reaction temperature is too high, there are impurities in the product to produce , all affect the productive rate of product, therefore, as a kind of preference, the reaction temperature in step (3) is 20-40 ℃; Available within hours.

The reaction described in step (4) is carried out in acetic acid; Reaction is incomplete when temperature of reaction is too low, when temperature of reaction is too high, impurity is produced in the product, all affects the productive rate of product, therefore, as a kind of preference, step The reaction temperature in (4) is 90-110 ℃; The reaction time is 10-20 hours.

The reaction of step (5) is carried out in methylene chloride or chloroform, and described oxygenant is m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid or potassium permanganate, is preferably hydrogen peroxide, will not involve during oxidation here To the carbon-carbon double bond, potassium permanganate can be used, and the oxidation is carried out under ice bath conditions, and the oxidation time is 30-60min.

The specific process of the above steps (1) to (5) is as follows:

(1) Use dichloromethane (DCM), chloroform or carbon disulfide as solvent, add sulfide anisole and catalyst at 0-20°C, add acetyl chloride dropwise under stirring condition, after the dropwise addition, warm up to room temperature (10-30°C), stirring for 10-20 hours; after the reaction, add crushed ice to the reaction solution, add concentrated hydrochloric acid dropwise to pH 1-3, stir at room temperature for 15 minutes, extract with dichloromethane, and wash the organic phase with water successively. Wash with saturated brine, remove the solvent and recrystallize the crude product obtained from a mixed solvent of petroleum ether and ethyl acetate to obtain the intermediate 4-methylthioacetophenone;

(2) Use tetrahydrofuran or N,N-dimethylformamide as solvent, add catalyst, after stirring for 10 minutes, add methyl benzoate, dropwise add 4-methylthioacetophenone, after dropwise addition, heat up to 50-70°C, stirring for 10-20 hours. After completion of the reaction, add water dropwise, then add dilute HCl to adjust the pH to 2-4, extract with _CH2Cl2 , dry over anhydrous sodium sulfate, and remove the solvent to obtain the crude product for silica gel column purification (petroleum ether: ethyl acetate = 50 _: 1), The intermediate 1-(4-methylthiophenyl)-3-phenyl-1,3-dione was obtained;

(3) Add tert-butyl nitrite (TBN) to the mixture of catalyst and 1-(4-methylthiophenyl)-3-phenyl-1,3 dione, stir at 20-40°C for 10-20 hours, after the reaction was completed, filtered, and the crude product obtained by removing the solvent was purified by a silica gel column (petroleum ether: ethyl acetate=40:1) to obtain the intermediate 1-(4-methylthiophenyl)-2-phenyl-1, 2 diketones, wherein tert-butyl nitrite can be easily prepared industrially by tert-butanol and sodium nitrite;

(4) Using acetic acid as a solvent, add 1-(4-methylthiophenyl)-3-phenyl-1,3 diketone, trifluoroacetaldehyde methyl hemiacetal and ammonium acetate, and react at 90-110°C After _10-20 hours, after the reaction is complete, add saturated _Na2CO3 solution to adjust the pH to 8-10, then extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent to obtain the crude product with silica gel Column purification (petroleum ether: ethyl acetate = 5:1) yielded the intermediate 4-[4-(methylthio)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole;

(5) Using dichloromethane as a solvent, add 4-[4-(methylthio)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole, and drop into it at 0°C Add an oxidizing agent such as a dichloromethane solution of m-chloroperoxybenzoic acid (mCPBA). After the dropwise addition, continue to stir in an ice bath for 30-60 minutes, add a saturated solution of sodium thiosulfate, extract with dichloromethane, and anhydrous Drying over sodium sulfate, spin off the organic solvent on a rotary evaporator, the resulting crude product was recrystallized with MeOH, and a white solid was obtained as the final product 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-( Trifluoromethyl)-1H-imidazole.

The reaction process of the synthetic method of the present invention is represented by chemical equation as shown in formula (5), wherein the catalyzer used in the step (1) is example with aluminum trichloride, and the catalyzer used in the step (2) is example with sodium hydride , the catalyzer used in the step (3) is example with iron trichloride, and the oxygenant used in the step (5) is example with m-chloroperoxybenzoic acid:

Beneficial effects of the present invention:

(1) The yield is high, the cost is low, and cheap raw materials and catalysts are used;

(2) avoid the generation of highly toxic cyanide, more friendly to the environment;

(3) The preparation of 1,2-diketone by 1,3-diketone avoids the destruction of the carbon-carbon double bond by the strong oxidizing agent KMnO ₄ , with few by-products.

Detailed ways

The productive rate in all following examples is calculated based on the substrate with a small molar amount

Example 1

Synthesis of step 1 4-methylthioacetophenone

Add sulfide anisole (25g, 200mmol) and dichloromethane (150mL) in 250mL round-bottomed flask; Add aluminum trichloride (40g, 300mmol) thereinto under stirring condition at 0 ℃, then slowly dropwise add acetyl chloride ( 16g, 15mL, 200mmol); after the dropwise addition was completed, it was naturally raised to room temperature and stirred for 12 hours. TLC (thin layer chromatography) showed that after the reaction was completed, the reaction solution was poured into crushed ice, and concentrated hydrochloric acid was added to adjust the pH to about 2. Stir at room temperature for 15 min, extract three times with dichloromethane, and combine the organic phases. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was spun off on a rotary evaporator, and the obtained crude product was recrystallized with a mixed solvent of petroleum ether and ethyl acetate to obtain 20 g of white solid 4-methylthioacetophenone with a yield of 60%.

¹ H NMR (400MHz, CDCl ₃ , TMS): δ7.87(d, 2H, J=8.8Hz), 7.27(d, 2H, J=8.8Hz), 2.57(s, 3H), 2.52(s, 3H ); ¹³ C NMR (125MHz, CDCl ₃ , TMS) 197.0, 145.8, 133.4, 128.6, 124.8, 26.3, 14.6.

Step 2 Synthesis of 1-(4-methylthiophenyl)-3-phenyl-1,3 diketone

Sodium hydride (60% 1.8g 45mmol) and dry tetrahydrofuran (30mL) were added to a 250mL single-necked flask; after stirring for 10min under ice bath, methyl benzoate (2.7g 19.8mmol) was added, and then 4-methylsulfide was added dropwise Base acetophenone (3g 18mmol); After dropwise addition, be warming up to 60 ℃, stir 12 hours. After TLC showed that the reaction was complete, water was added dropwise to the reaction system to quench the reaction, then dilute hydrochloric acid was added to adjust the pH to about 3, extracted three times with dichloromethane, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the resulting crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 50:1) to obtain a yellow solid 1-(4-methylthiobenzene)-3-phenyl-1, 3.1 g of diketone, yield 63%.

¹ H NMR (400MHz, CDCl ₃ , TMS): δ16.93(s, 1H), 7.97-7.99(m, 2H), 7.91(d, 2H, J=8.4Hz), 7.55(t, 1H, J= 7.6Hz), 7.49(t, 2H, J=7.6Hz), 7.30(d, 2H, J=8.0Hz), 6.82(s, 1H), 2.54(s, 3H); ¹³ C NMR (125MHz, CDCl ₃ , TMS): δ185.4, 184.9, 145.1, 135.4, 132.3, 131.6, 128.6, 127.4, 127.0, 125.2, 92.6, 14.8.

Step 3 Synthesis of 1-(4-methylthiophenyl)-2-phenyl-1,2 dione

Add ferric chloride (128mg, 0.8mmol), 1-(4-methylthiophenyl)-3-phenyl-1,3 dione (1.1g, 4mmol) and tert-butyl nitrite (2g , 19 mmol), stirred at 30°C for 12 hours. After TLC showed that the reaction was complete, the diatomaceous earth was filtered, and the solvent was spin-dried, and the obtained crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 40:1) to obtain a yellow solid 1-(4-methylthiobenzene)-2- Phenyl-1,2-dione 768 mg, yield 74%.

¹ H NMR (400MHz, CDCl ₃ , TMS): δ7.96(dd, 2H, J=8.4, 1.2Hz), 7.87(d, 2H, J=8.4Hz), 7.65(t, 1H, J=7.6Hz ), 7.50 (t, 2H, J=7.6Hz), 7.28-7.30 (m, 2H), 2.52 (s, 3H); ¹³ C NMR (125MHz, CDCl ₃ , TMS): 194.5, 193.4, 148.9, 134.7, 133.0, 130.0, 129.8, 129.1, 128.9, 125.0, 14.5.

Step 4 Synthesis of 4-[4-(methylthio)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole

To a 25 mL round bottom flask was added 1-(4-methylthiophenyl)-3-phenyl-1,2 dione (512 mg, 2 mmol), trifluoroacetaldehyde methyl hemiacetal (572 mg, 4 mmol), acetic acid Ammonium (462 mg, 6 mmol) and acetic acid (5 mL), refluxed at 110° C. for 12 hours. After TLC showed that the reaction was complete, saturated Na ₂ CO ₃ solution was added to adjust the pH to about 9, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was removed on a rotary evaporator, and the resulting crude product was purified on a silica gel column (PE:EA=5:1) to obtain a white solid 4-[4-(methylthio)phenyl]-5-phenyl-2- (Trifluoromethyl)-1H-imidazole 370 mg, yield 55%.

¹ H NMR (400 MHz, DMSO-d6, TMS): δ13.84 (br, 1H), 7.23-7.55 (m, 9H), 2.56 (s, 3H); MS (EI, M/e): 334.

Step 5 Synthesis of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole

Add 4-[4-(methylthio)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole (167mg, 0.5mmol) in dichloromethane (10mL) at 0°C Add m-chloroperoxybenzoic acid (75%, 241 mg, 1.05 mmol) in dichloromethane (10 mL) dropwise to the solution; after the dropwise addition, continue stirring for 30 min under ice-bath conditions, and add a saturated solution of sodium thiosulfate; Extracted three times with dichloromethane, dried over anhydrous sodium sulfate; the organic solvent was spin-off on a rotary evaporator, and the resulting crude product was recrystallized with MeOH to obtain a white solid 4-[4-(methylsulfonyl)phenyl]-5- Phenyl-2-(trifluoromethyl)-1H-imidazole 158 mg, yield 86%.

¹ H NMR (400MHz, DMSO-d6, TMS): δ14.00 (br, 1H), 7.49-7.73 (m, 9H), 2.76 (s, 3H), MS (ESI, (MH) ^- ): 364.9. .

Example 2

Synthesis of step 1 4-methylthioacetophenone

Add sulfide anisole (25g, 200mmol) and dichloromethane (150mL) in 250mL round-bottomed flask; Add iron trichloride (80g, 500mmol) therein under stirring condition at 0 ℃, then slowly add acetyl chloride ( 32g, 30mL, 400mmol); after the dropwise addition was completed, it was naturally raised to room temperature and stirred for 12 hours. TLC showed that after the reaction was completed, the reaction solution was poured into crushed ice, and concentrated hydrochloric acid was added to adjust the pH to about 2. Stir at room temperature for 15 min, extract three times with dichloromethane, and combine the organic phases. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was spun off on a rotary evaporator, and the obtained crude product was recrystallized from a mixed solvent of petroleum ether and ethyl acetate to obtain 14 g of white solid 4-methylthioacetophenone with a yield of 42%.

Step 2 Synthesis of 1-(4-methylthiophenyl)-3-phenyl-1,3 diketone

Sodium hydride (60%, 1.4 g, 36 mmol) and dry tetrahydrofuran (30 mL) were added to a 250 mL one-necked flask. After stirring in an ice bath for 10 min, add methyl benzoate (1.2 g, 9 mmol), and then add dropwise 4-methylthioacetophenone (3 g, 18 mmol); after the dropwise addition, raise the temperature to 60° C., and stir for 12 hours . After TLC showed that the reaction was complete, water was added dropwise to the reaction system to quench the reaction, then dilute hydrochloric acid was added to adjust the pH to about 3, extracted three times with dichloromethane, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the resulting crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 50:1) to obtain a yellow solid 1-(4-methylthiobenzene)-3-phenyl-1, 3 diketone 1.8g, yield 74% (relative to the substrate methyl benzoate with a small molar amount).

Step 3 Synthesis of 1-(4-methylthiophenyl)-2-phenyl-1,2 dione

Ferrous chloride (51 mg, 0.4 mmol), 1-(4-methylthiophenyl)-3-phenyl-1,3 dione (1.1 g, 4 mmol) and tert-butyl nitrite (1.2 g, 12mol), stirred at 30°C for 12 hours. After TLC showed that the reaction was complete, the diatomaceous earth was filtered, and the solvent was spin-dried, and the obtained crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 40:1) to obtain a yellow solid 1-(4-methylthiobenzene)-2- Phenyl-1,2-dione 531 mg, yield 51%.

Step 4 Synthesis of 4-[4-(methylthio)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole

To a 25 mL round bottom flask was added 1-(4-methylthiophenyl)-3-phenyl-1,2 dione (512 mg, 2 mmol), trifluoroacetaldehyde methyl hemiacetal (314 mg, 2.2 mmol), Ammonium acetate (127mg, 2.2mmol) and acetic acid (5mL) were refluxed at 110°C for 12 hours. After TLC showed that the reaction was complete, saturated Na ₂ CO ₃ solution was added to adjust the pH to about 9, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the obtained crude product was purified on a silica gel column (PE:EA=5:1) to obtain a white solid 4-[4-(methylthio)phenyl]-5-phenyl-2- (Trifluoromethyl)-1H-imidazole 290 mg, yield 43%.

Step 5 Synthesis of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole

Add 4-[4-(methylthio)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole (167mg, 0.5mmol) in dichloromethane (10mL) at 0°C A solution of hydrogen peroxide (30%, 102 mg, 0.9 mmol) in dichloromethane (10 mL) was dropped into the solution. After the dropwise addition was completed, stirring was continued for 30 min under ice-bath conditions, and a saturated solution of sodium thiosulfate was added. Extracted three times with dichloromethane and dried over anhydrous sodium sulfate. The organic solvent was spinned off on a rotary evaporator, and the resulting crude product was recrystallized from MeOH to give 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H as a white solid - Imidazole 124 mg, yield 68%.

Example 3

Synthesis of step 1 4-methylthioacetophenone

Add sulfide anisole (25g, 200mmol) and chloroform (150mL) in 250mL round-bottomed flask; Add aluminum trichloride (32g, 240mmol) therein under stirring condition at 0 ℃, then slowly add acetyl chloride ( 8g, 7.5mL, 100mmol); after the dropwise addition, it was naturally raised to room temperature and stirred for 12 hours. TLC showed that after the reaction was completed, the reaction solution was poured into crushed ice, and concentrated hydrochloric acid was added to adjust the pH to about 2. Stir at room temperature for 15 min, extract three times with dichloromethane, and combine the organic phases. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was spun off on a rotary evaporator, and the obtained crude product was recrystallized with a mixed solvent of petroleum ether and ethyl acetate to obtain 17 g of white solid 4-methylthioacetophenone with a yield of 51%.

Step 2 Synthesis of 1-(4-methylthiophenyl)-3-phenyl-1,3 diketone

Sodium hydride (60%, 2.9g, 72mmol) and dry tetrahydrofuran (30mL) were added into a 250mL single-necked flask; after stirring for 10min under ice bath, methyl benzoate (4.9g, 36mmol) was added, and then 4- Methylthioacetophenone (3 g, 18 mmol); after the dropwise addition, the temperature was raised to 60° C. and stirred for 12 hours. After TLC showed that the reaction was complete, water was added dropwise to the reaction system to quench the reaction, then dilute hydrochloric acid was added to adjust the pH to about 3, extracted three times with dichloromethane, and dried over anhydrous sodium sulfate. The organic solvent was spin-off on a rotary evaporator, and the resulting crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 50:1) to obtain a yellow solid 1-(4-methylthiobenzene)-3-phenyl-1, 3.1 g of diketone, yield 63%.

Step 3 Synthesis of 1-(4-methylthiophenyl)-2-phenyl-1,2 dione

Add ferric oxide (319 mg, 2 mmol), 1-(4-methylthiophenyl)-3-phenyl-1,3 dione (1.1 g, 4 mmol) and tert-butyl nitrite (2.9 g , 28 mmol), stirred at 30°C for 12 hours. After TLC showed that the reaction was complete, the diatomaceous earth was filtered, and the solvent was spin-dried, and the obtained crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 40:1) to obtain a yellow solid 1-(4-methylthiobenzene)-2- Phenyl-1,2-dione 596 mg, yield 57%.

Step 4 Synthesis of 4-[4-(methylthio)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole

To a 25 mL round bottom flask was added 1-(4-methylthiophenyl)-3-phenyl-1,2 dione (512 mg, 2 mmol), trifluoroacetaldehyde methyl hemiacetal (429 mg, 3 mmol), acetic acid Ammonium (385 mg, 5 mmol) and acetic acid (5 mL), refluxed at 110° C. for 12 hours. After TLC showed that the reaction was complete, saturated Na ₂ CO ₃ solution was added to adjust the pH to about 9, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was removed on a rotary evaporator, and the resulting crude product was purified on a silica gel column (PE:EA=5:1) to obtain a white solid 4-[4-(methylthio)phenyl]-5-phenyl-2- (Trifluoromethyl)-1H-imidazole 335 mg, yield 50%.

Step 5 Synthesis of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole

Add 4-[4-(methylthio)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole (167mg, 0.5mmol) in dichloromethane (10mL) at 0°C A solution of potassium permanganate (172 mg, 1.1 mmol) in dichloromethane (10 mL) was dropped into the solution. After the dropwise addition was completed, stirring was continued for 30 min under ice-bath conditions, and a saturated solution of sodium thiosulfate was added. Extracted three times with dichloromethane and dried over anhydrous sodium sulfate. The organic solvent was spinned off on a rotary evaporator, and the resulting crude product was recrystallized from MeOH to give 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H as a white solid - Imidazole 115 mg, yield 63%.

The products in each reaction step in Example 2 and Example 3 were compared by TLC and determined to be consistent with the product obtained in each reaction step corresponding to Example 1.

Claims (1)

1. synthetic 4-[4-(methylsulfonyl) phenyl] method of-5-phenyl-2-(trifluoromethyl)-1H-imidazoles, it is characterized in that, step is as follows:

(1) in 250mL round-bottomed flask, add thioanisole 25g and methylene dichloride 150mL; Under 0 ℃ of agitation condition, add wherein aluminum chloride 40g, then slowly drip Acetyl Chloride 98Min. 16g; After dropwising, naturally rise to room temperature, stir 12 hours, after TLC shows that reaction finishes, by reaction solution impouring trash ice, then add concentrated hydrochloric acid to adjust pH to 2 left and right, under room temperature, stir 15min, use dichloromethane extraction three times, merge organic phase; Organic phase washes with water successively, saturated common salt washing, and anhydrous sodium sulfate drying revolves except organic solvent on Rotary Evaporators, and the mixed solvent recrystallization of sherwood oil and ethyl acetate for gained crude product, obtains white solid 4-methylthio phenyl ethyl ketone 20g, productive rate 60%;

(2) to adding 60% sodium hydride 1.8g and dry tetrahydrofuran (THF) 30mL in 250mL single port flask; Under ice bath, stir after 10min, add methyl benzoate 2.7g, and then drip 4-methylthio phenyl ethyl ketone 3g; After dropwising, be warming up to 60 ℃, stir 12 hours; After TLC shows and reacts completely, to dripping the shrend reaction of going out in this reaction system, then add dilute hydrochloric acid to be adjusted to about pH3, dichloromethane extraction three times, anhydrous sodium sulfate drying; On Rotary Evaporators, revolve except organic solvent, gained crude product is purified with silicagel column, the sherwood oil that leacheate is 50:1: the mixed solvent of ethyl acetate, obtains yellow solid 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone 3.1g, productive rate 63%;

(3) in test tube, add iron trichloride 128mg, 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone 1.1g and nitrite tert-butyl 2g, stir 12 hours in 30 ℃; After TLC demonstration reacts completely, diatomite filtration, is spin-dried for solvent, gained crude product silicagel column purifying, the sherwood oil that leacheate is 40:1: the mixed solvent of ethyl acetate, obtains yellow solid 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone 768mg, productive rate 74%;

(4) in 25mL round-bottomed flask, add 1-(4-methylthio phenyl)-3-phenyl-1,2 diketone 512mg, trifluoro acetaldehyde methyl hemiacetal 572mg, ammonium acetate 462mg and acetic acid 5mL, 110 ℃ are refluxed 12 hours; After TLC demonstration reacts completely, add saturated Na ₂cO ₃solution is adjusted to pH9 left and right, and ethyl acetate extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying; On Rotary Evaporators, revolve except organic solvent, gained crude product silicagel column purifying, leacheate is the sherwood oil of 5:1: the mixed solvent of ethyl acetate, obtains white solid 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 370mg, productive rate 55%;

(5) at 0 ℃, to 4-[4-(methylthio group) phenyl] drip the 10mL dichloromethane solution of 75% metachloroperbenzoic acid 241mg in the 10mL dichloromethane solution of-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 167mg; After dropwising, continue to stir 30min under condition of ice bath, add the saturated solution of Sulfothiorine; With dichloromethane extraction three times, anhydrous sodium sulfate drying; On Rotary Evaporators, revolve except organic solvent, gained crude product MeOH recrystallization, obtains white solid 4-[4-(methylsulfonyl) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 158mg, productive rate 86%.